Zika virus is a member of the arbovirus
Flaviviridae
family transmitted by
Aedes
mosquitos and it is associated with microcephaly in infants born to infected mothers.
Wolbachia
is an intracellular gram-negative alpha-proteobacteria that infects many species of arthropods, including mosquitos. The presence of
Wolbachia
in mosquitos has been shown to control the vector population and suppress arbovirus transmission. One mechanism of
Wolbachia
-mediated interference with virus replication is competition over host resources between
Wolbachia
and the virus. We hypothesize that cholesterol metabolism is involved in
Wolbachia
-mediated virus suppression due to its important role in Zika virus replication. In this study, we determined that
Wolbachia
impacted virus replication by altering cholesterol biosynthesis in
Aedes albopictus
C6/36 cells, diverting resources from the host cell mevalonate (MVA) pathway to fulfill the needs of the bacteria. This resulted in a decrease of total cholesterol, increased
Wolbachia
loads, and decreased viral titers. Inhibition of the MVA pathway using fluvastatin decreased total cholesterol and viral titers, mimicking the effects of
Wolbachia
on the virus in
Wolbachia-
free cells. We also found that
Wolbachia-
infected cells had depleted lipid droplets, the main component of which is cholesterol esters. We confirmed that cholesterol esterases were upregulated in response to virus infection in C6/36 cells. Functional analysis showed that alteration of cholesterol metabolism simulated
Wolbachia
-mediated inhibition of virus infection in C6/36 cells. Our study provides a mechanism behind
Wolbachia
-induced interference of arbovirus replication and could help advance strategies to control arbovirus pathogens in insect vectors and human infections.
IMPORTANCE
Arthropod-borne viruses are emerging pathogens that are spread widely by mosquitos. Zika virus is an arbovirus that can infect humans and be transmitted from an infected mother to the fetus, potentially leading to microcephaly in infants. One promising strategy to prevent disease caused by arboviruses is to target the insect vector population. Recent field studies have shown that mosquito populations infected with
Wolbachia
bacteria suppress arbovirus replication and transmission. Here, we describe how intracellular bacteria redirect resources within their host cells and suppress Zika virus replication at the cellular level. Understanding the mechanism behind
Wolbachia
-induced interference of arbovirus replication could help advance strategies to control arbovirus pathogens in insect vectors and human populations.